The beta-hemoglobinopathies (sickle cell disease and beta-thalassemia) are the most common genetic diseases in the world. The symptoms of these diseases can be ameliorated or eliminated by pharmacological induction of fetal hemoglobin (Hb F) expression. Butyrate induces high levels of Hb F in many patients, but must be given only at intermittent intervals (pulsed) because it inhibits erythroid cell growth. This antiproliferative activity limits its potential use in inducing gamma-globin, because drug administration must be limited to intermittent use. The short half-life of the drug and the need for IV administration further limits its general utility. The applicant's goal is to develop an Hb F-inducing compound which does not inhibit cell growth, has a long half-life, and is active when administered orally, as a more effective therapeutic. A plan is described for preclinical investigation of new compounds which provide potential advantages over existing Hb F stimulants. Lead compounds from three chemical classes have been shown to: 1) induce Hb F in vitro to a similar level as does butyrate; 2) stimulate F-reticulocytes in vivo in baboons; and 3) be metabolically stable and reach adequately high and sustained plasma levels after oral administration. Furthermore, three new lead compounds and chemical classes avoid the adverse properties of butyrate itself in that they do not inhibit erythroid progenitor cell growth. The chemical classes of these three compounds can serve as backbone structures for additional modification to theoretically further enhance potential therapeutic properties, if necessary. The sequential studies as detailed in this proposal will determine if these three lead compounds may themselves be optimal for development, or whether any of the other derivatives they have synthesized have an even more attractive profile for clinical development. PROPOSED COMMERCIAL APPLICATION: An oral therapeutic which will ameliorate the clinical symptoms of sickle cell anemia and the anemia of beta thalassemia.